Pervasive hitchhiking at coding and regulatory sites in humans

Much effort and interest have focused on assessing the
importance of natural selection, particularly positive natural
selection, in shaping the human genome. Although scans for positive
selection have identified candidate loci that may be associated
with positive selection in humans, such scans do not indicate
whether adaptation is frequent in general in humans. Studies based
on the reasoning of the MacDonald-Kreitman test, which, in
principle, can be used to evaluate the extent of positive
selection, suggested that adaptation is detectable in the human
genome but that it is less common than in Drosophila or Escherichia
coli. Both positive and purifying natural selection at functional
sites should affect levels and patterns of polymorphism at linked
nonfunctional sites. Here, we search for these effects by analyzing
patterns of neutral polymorphism in humans in relation to the rates
of recombination, functional density, and functional divergence
with chimpanzees. We find that the levels of neutral polymorphism
are lower in the regions of lower recombination and in the regions
of higher functional density or divergence. These correlations
persist after controlling for the variation in GC content, density
of simple repeats, selective constraint, mutation rate, and depth
of sequencing coverage. We argue that these results are most
plausibly explained by the effects of natural selection at
functional sites -- either recurrent selective sweeps or background
selection -- on the levels of linked neutral polymorphism. Natural
selection at both coding and regulatory sites appears to affect
linked neutral polymorphism, reducing neutral polymorphism by 6%
genome-wide and by 11% in the gene-rich half of the human genome.
These findings suggest that the effects of natural selection at
linked sites cannot be ignored in the study of neutral human
polymorphism.